In the case of pancreatic cancer, early systemic dissemination, extraordinary local invasion, late diagnosis, and poor response to the existing chemotherapeutics contribute to an adverse patient prognosis. There is an urgent need to identify novel therapies that can significantly improve survival in patients. Tumor cells acquire as array of genetic, signaling, and epigenetic alterations that allow tumor cells to survive in harsh conditions and contribute to tumor progression, metastasis, and overall poor therapeutic response. Inhibiting the ability of tumor cells to survive in adverse conditions would diminish tumor progression and metastasis. Increasing evidence shows that tumor cells are reliant on certain nutrients in a manner dissimilar to non- transformed cells. We have identified that stabilization and activation of hypoxia-inducible factor-1 alpha by MUC1, an oncogene that confers aggressiveness in pancreatic cancer, contribute to the metabolic reprograming resulting in poor response to therapy. We have also observed that MUC1 regulates tumor cell metabolite exchange with stellate cells, a major constituent of desmoplasia in pancreatic tumors, thus facilitating tumor cell survival in low pH conditions. While abolishing the fibrotic stroma altogether could make tumors more invasive, novel therapeutic opportunities may be obtained by targeting specific features of the stellate cells that provide nutritional support for tumor cell survival in harsh conditions. Hence, we propose to investigate the efficacy of blocking the MUC1-mediated tumor-stromal metabolic crosstalk, which facilitates aggressiveness in pancreatic cancer. Such mechanisms regulate tumor cell growth and invasiveness in low pH conditions. Thus, these studies will promote the development of new and more effective treatment for metastatic pancreatic cancer. Our long-term goal is to determine the molecular basis of MUC1-mediated tumor-stromal metabolic cross- talk and how it facilitates invasiveness and metastasis in pancreatic cancer. In the first aim, we will investigate the impact of halting the utilization of stellate cell-secreted metabolites by tumor cells during pancreatic cancer progression and metastasis. In the second aim, we will elucidate the biochemical and molecular basis for MUC1- mediated activation of the transcriptional reprogramming that contributes to survival in low pH conditions, in response to stellate cell-secreted factors. In the third aim, we will investigate the potential of novel therapies that target the production of metabolites in stellate cells to support tumor cell survival in low pH conditions. Collectively, the proposed studies employ an innovative and integrative approach to determine the metabolic and signaling basis of MUC1-mediated tumor-stromal metabolic interactions that facilitate tumor progression and metastasis. Further, these studies will uncover novel therapeutic strategies to treat aggressive pancreatic cancer.